scholarly journals Phase II Window Study of Pembrolizumab in Untreated B-Cell Non-Hodgkin Lymphoproliferative Diseases

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5258-5258
Author(s):  
Ajay K. Gopal ◽  
Adam Greenbaum ◽  
Ryan C. Lynch ◽  
Edus H. Warren ◽  
Chaitra S. Ujjani ◽  
...  
Keyword(s):  
T Cell ◽  
Partial Response ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Response Rate ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Complete Response ◽  
Non Hodgkin Lymphoma

INTRODUCTION While chemoimmunotherapy is effective in indolent B-cell non-Hodgkin lymphoma (iBCL), most patients are older and may benefit from a chemotherapy-free approach. Pembrolizumab is an immune checkpoint inhibitor which blocks the PD-1 receptor. Upon chronic antigen stimulation, T-cells can lose their anti-tumor activity due to PD-1 signaling. Multiple in vitro and in vivo studies have demonstrated that blockade of PD-1 can reverse the T-cell dysfunction induced by the tumor microenvironment. Pembrolizumab has shown an excellent safety and toxicity profile. Pembrolizumab as a single agent is FDA approved for numerous solid tumors and some lymphoma subtypes including Hodgkin lymphoma and primary mediastinal B-cell lymphoma. PD-1 inhibitors have also shown activity in the relapsed/refractory iBCL with overall responses reported to range from 10 to 60% (Ding et al., 2017; Lesokhin et al., 2016; Nastoupil et al., 2017a). However, the overwhelming majority of the patients in these studies had received prior chemotherapy. Patients with untreated iBCL have a relatively intact immune system and may have a greater capacity to mount an effective anti-tumor immune response upon reversal of T-cell dysfunction. OBJECTIVES The primary objective is evaluate the efficacy of pembrolizumab as monotherapy for patients with untreated iBCL based on ORR measured at the end of a 6-cycle treatment period. Secondary objective include: Safety and toxicity.Efficacy including complete response, clinical benefit rate (complete response + partial response + stable disease) ≥6 months, time to next therapy, progression-free survival, and duration of response. SUBJECTS AND METHODS Patients ≥ 18 years of age with previously untreated radiographically measurable follicular or marginal zone lymphoma with an indication for treatment are included. These indications include significant symptoms, end organ damage, cytopenias, or steady progression. Major exclusions include known autoimmune disease, major organ dysfunction, or ECOG ≥ 2. Treatment consists of 200 mg pembrolizumab IV on day 1 of each 21-day cycle. Initial response assessment occurs after 6 cycles. Patients with a complete or partial response can remain on the trial. Patients who have stable disease or progressive disease and are asymptomatic (excluding hyperprogression) will receive 3 additional cycles and then will be restaged to account for a delayed response. Those patients with a complete or partial response after those additional cycles can remain on the trial. Subsequently, response assessment occurs every 3 cycles. Patients without progressive disease or unacceptable toxicity are able to continue up to 18 cycles. Up to 33 patients will be enrolled, and follow-up may continue for an additional 2 years. STATISTICAL METHODS The primary efficacy endpoint is the overall response rate (CR + PR). Secondary endpoints include duration of response, progression free survival, and time to next therapy (see treatment schema). A sample size of 33 participants is planned to provide 80% power at the 5% significance level to distinguish the observed overall response rate from a true rate of ≥ 40% versus ≤ 20%) using a Simon 2-stage minimax design. The trial will be terminated early if fewer than 5 of the first 18 patients have a response. The thresholds used in this design are based on what is considered to be a clinically meaningful response rate with a novel agent with very low rates of adverse events and toxicity compared to standard regimens. This response rate threshold is also higher than what has been observed using anti-PD-1 therapy in the relapsed/refractory setting. RECRUITMENT Three patients have been accrued to the study. To date, all patients have remained on study with no grade 3-5 adverse events. CORRELATIVE STUDIES Given that pembrolizumab is known to modulate the tumor immune microenvironment, we are also performing clinical correlates on a companion protocol. Using several 22 color flow cytometry panels and 6-color multiplex immunohistochemistry, we will analyze pre- and post-treatment lymph nodes and peripheral blood. These studies will examine over 50 populations of immune cells in addition to T-cell activation/exhaustion markers such as PD-1, TIM-3, LAG-3, CTLA-4, and PD-L1. TRIAL REGISTRATION Clinicaltrials.gov (NCT03498612). Funding for both the trial and correlative studies has been provided by Merck. Figure Disclosures Gopal: Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding. Lynch:Rhizen Pharmaceuticals S.A: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; T.G. Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Juno Therapeutics: Research Funding. Ujjani:Pharmacyclics: Honoraria; PCYC: Research Funding; Astrazeneca: Consultancy; Atara: Consultancy; Gilead: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding. Shadman:ADC Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Sound Biologics: Consultancy; Mustang Bio: Research Funding; TG Therapeutic: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Gilead: Consultancy, Research Funding; Celgene: Research Funding; AbbVie: Consultancy, Research Funding; Acerta Pharma: Research Funding; BeiGene: Research Funding; Sunesis: Research Funding; Astra Zeneca: Consultancy; Atara Biotherapeutics: Consultancy. Smith:Denovo Biopharma: Research Funding; Incyte Corporation: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Ignyta (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Ayala (spouse): Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Fromm:Merck, Inc.: Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding. OffLabel Disclosure: Pembrolizumab for the treatment of indolent non-Hodgkin lymphoma

scholarly journals Ixazomib in Previously Untreated Indolent B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5326-5326
Author(s):  
Solomon A. Graf ◽  
Ryan C. Lynch ◽  
David G. Coffey ◽  
Mazyar Shadman ◽  
Sandra Kanan ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Response Assessment ◽  
Clinical Indication ◽  
Non Hodgkin Lymphoma ◽  
Tumor Reduction ◽  
Frontline Treatment ◽  
Grade 3 ◽  
Indication For Treatment

Abstract Background: Frontline treatment of indolent B-cell non-Hodgkin lymphoma (iB-NHL) typically involves intravenously administered anti-CD20 monoclonal antibodies with or without cytotoxic chemotherapy. Effective and low-toxicity therapies with improved convenience of administration are sought. We hypothesized that ixazomib (Ix) could safely and conveniently induce remissions in patients with untreated iB-NHL. Here we present the first data on frontline use of Ix in untreated iB-NHL. Methods: This single-arm, open-label phase II "window" trial for patients with untreated iB-NHL (NCT02339922) opened to enrollment in May 2016. Eligibility included histopathologically confirmed iB-NHL, measurable disease, a clinical indication for treatment based on NCCN guidelines, and no prior systemic treatment. Ix was administered at 4 mg orally once a week on consecutive 28-day cycles until disease progression or unacceptable toxicity and four doses of weekly rituximab (R) were added during the 7th cycle, after the initial window period. The primary endpoint was investigator-assessed response rate after independent radiology review. Response assessment occurred at every 2 cycles and using standard (Lugano) criteria. Tumor tissue was collected for gene expression profiling and immunohistochemical evaluation of molecular pathways associated with proteasome inhibition. Results: As of July 1, 2018, 15 patients were treated. The median age was 64 years (range, 47 to 81) and 53% were men. Disease histologies included follicular lymphoma (FL, n = 10), mantle cell lymphoma (MCL, n = 2), marginal zone lymphoma (MZL, n = 2), and small lymphocytic lymphoma (SLL, n = 1). At the start of therapy, all had stage III/IV disease and B-symptoms were present in 40%. For patients with FL, 80% had poor risk by FLIPI. Overall, the indication for treatment included symptoms due to disease (40%), steady progression of disease (33%), and cytopenia due to disease (27%). To date, 14 patients were evaluable for response and 13 experienced tumor burden reduction during the Ix-only window (Figure 1). Of patients with FL, 6 completed the Ix-only window phase and, of these, 5 achieved PR. An additional 4 patients with FL have not completed all 6 cycles of Ix monotherapy. Of these, 1 patient achieved a PR after 4 cycles and continues on treatment, 1 patient came off study with stable disease after 4 cycles, and 2 patients have experienced tumor reduction without meeting formal response criteria and continue on treatment (after 2 and 4 cycles, respectively). Of those patients with FL that received R, all achieved formal remission (3 CR, 3 PR). Median progression free survival has not been reached with a median follow up of 7.4 months. No patient with non-FL histology had yet achieved a PR during the Ix-only window or had undergone response assessment after receiving R at the time of the data cut. The most common adverse events (AEs) for all pts were grade 1-2 and included nausea (53%), diarrhea (53%), rash (40%), and fatigue (33%). Peripheral neuropathy occurred in 20% patients (grade 2 in 7%). A single grade ≥ 3 AE occurred (syncope, grade 3). Conclusions: Data from this interim analysis suggest that Ix monotherapy is well tolerated and highly active in the frontline treatment of FL with all patients demonstrating tumor reduction to date and augmented responses following the addition of R. Non-FL histologies of B-NHL appear less responsive to Ix, but numbers are small. Accrual on study continues. Correlative analyses are underway to determine if Ix or Ix-R may represent a viable frontline option for some patients with iB-NHL. Figure 1. Waterfall plot of response. Number of cycles of treatment received to date indicated for each subject. Four weekly doses of rituximab are added, per protocol, with the 7th cycle of ixazomib. Asterisk indicates treatment on study ongoing. Disclosures Graf: Acerta: Research Funding; TG Therapeutics: Research Funding; Beigene: Research Funding. Lynch:T.G. Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Shadman:Genentech: Consultancy; Genentech: Research Funding; Verastem: Consultancy; AbbVie: Consultancy; Gilead Sciences: Research Funding; Beigene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; AstraZeneca: Consultancy; TG Therapeutics: Research Funding; Mustang Biopharma: Research Funding; Pharmacyclics: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding. Gopal:Pfizer: Research Funding; Aptevo: Consultancy; BMS: Research Funding; Brim: Consultancy; Asana: Consultancy; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Takeda: Research Funding; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Incyte: Consultancy; Teva: Research Funding.

scholarly journals Early Response Observed in Pediatric Patients with Refractory/Relapsed B-Cell Non-Hodgkin Lymphoma Treated with Sequential Chimeric Antigen Receptor T Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1945-1945 ◽  
Author(s):  
Wenqun Zhang ◽  
Bo Hu ◽  
Ling Jing ◽  
Jing Yang ◽  
Shan Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Pediatric Patients ◽  
Response Rate ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T ◽  
To Receive

Background:Outcomes for pediatric patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) are poor despite use of high-intensity chemotherapy. CAR-T has shown efficacy in treating refractory/relapsed leukemia in pediatric patients and non-Hodgkin lymphoma in adult patients. Objectives:To assess the safety and efficacy of sequential CAR-T in the treatment of refractory/ relapsed B-NHL in pediatric patients. Design/Methods:In our ongoing clinical trial (ChiCTR1800014457), we enrolled and treated 17 pediatric patients with refractory/relapsed B-NHL. Following leukapheresis, T cells were activated with CD3 and CD28 antibodies for 24h, then transduced with lentivirus encoding anti-CD19-CD3zeta-4-1BB CAR and cultured for 5-6 days in serum-free media containing IL2, IL7, IL15, IL21. Meanwhile, all patients briefly received lympho-depleting chemotherapies consisting of fludarabine (30 mg/m2/day) and cyclophosphamide (250 mg/m2/day) on days −5, −4 and −3 according to tumor burden and patient state. On day 0, all patients received a single-dose infusion of CAR-T cells. CAR-T cell dose ranged from 0.5 to 3 million/kg. CAR-T cell numbers and cytokines were measured weekly. Tumor responses were evaluated at day 30 and day 60 post infusion and every two months thereafter. Adverse events were graded according to CTCAEv4 except cytokine release syndrome (CRS) was graded according to Lee et al. Results:Treated patients had relapsed/refractory Burkitt lymphoma (BL) (13/17), diffuse large B cell lymphoma (DLBCL) (2/17), B-lymphoblastic lymphoma (B-LBL) (2/17), and ranged from 4.5-18.0 years old. By St Jude's staging, 9 cases (46.7%) were in stage III, 8 cases (53.3%) were in stage IV. There were 3 cases with CNS involvement (17.6%) and 7 cases with bone marrow involvement (41.2%). They all failed at prior treatment including an average of 8.9 (6-15) courses of chemotherapy. They were then treated with sequential CAR-T cell therapy. A total of 26 courses of CAR-T cell infusion were administered. The overall complete response rate (CRR) was 41.7% (7/17) when first course of CAR-T therapy was conducted, which were all CD19 targeted. Among the 10 patients who did not achieve CR, 2 patients achieved PR with ongoing response, 1 patient died of severe CRS and progression at day 6 and another patient refused to continue the following therapy when tumor progressed at day 99, and he died 1 week later, the other 6 continued to receive second course of CAR-T therapy targeting CD20 or CD22, and 3 of them achieved CR. Thus the overall CRR increased to 58.8% (10/17). The 3 patients, who still did not achieve CR, continued to receive third course of CAR-T therapy targeting CD20 or CD22. Two of them finally achieved CR and the other failed to get CR and is now retreated with chemotherapy and oral Olaparib and Venclexta. Thus, with a median follow-up of 6.2 months (1-18 months), the overall response rate of sequential CAR-T therapy was 94.1% (16/17) and the overall CRR was 70.6% (12/17). Toxicity information through day 30 revealed the occurrence of mild CRS in 8 subjects (47.1%, grade I n=8, grade II n=0), severe CRS in 9 subjects (52.9%, grade III n=8, grade IV n=1). Neurotoxicity was observed in 7 cases (41.2%, seizure in 3 cases, tremor in 4 cases, headache in 1 cases). One case who died rapidly at day 6 of therapy suffered severe CRS (high fever, Capillary leak syndrome, severe pleural effusion, respiratory failure, shock, cardiopulmonary arrest) and neurotoxicity besides disease progression. Other patients with severe CRS and neurotoxicity recovered fully after glucocorticoid use and symptomatic treatment including anti-epilepsy, fluid, dehydrating agent. No case used tocilizumab. Response assessments were performed at day 15, 30, 45, 60. Updated enrollment, toxicity and response assessments will be presented. Conclusion: CD19/CD20/CD22-CAR-T therapy showed promising efficacy for pediatric patients with r/r B-NHL and the toxicities are tolerable with proper symptomatic and supportive treatment. Sequential CAR-T therapy can improve the efficacy compared with a single course of CAR-T infusion. Disclosures No relevant conflicts of interest to declare.

Phase I/II Trial of Ofatumumab/Lenalidamide for Patients with Relasped/Refractory B-Cell Non-Hodgkin Lymphoma: High Response Rate in Indolent Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3692-3692
Author(s):  
Julie M Vose ◽  
Fausto R. Loberiza ◽  
R. Gregory Bociek ◽  
Philip Bierman ◽  
James O. Armitage
Keyword(s):  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
High Response Rate ◽  
Indolent Lymphoma ◽  
Non Hodgkin Lymphoma

Abstract Abstract 3692 Introduction: Lenalidomide and ofatumumab have demonstrated clinical activity as single agents in a variety of types of non-Hodgkin lymphoma (NHL). This trial is a phase I/II trial combining these two agents for treatment of patients with relapsed and refractory B-cell NHL. Methods: Patients with relapsed and refractory B-cell NHL of any histology were enrolled on a phase I/II trial combining lenalidomide and ofatumumab. Nine patients were on the phase I part of the trial and received a fixed dose of ofatumumab 1000 mg weekly × 8 doses along with lenalidomide 15 mg (N=3), or10 mg (N=6) for 21/28 days until the time of progression. The phase II portion of the study has 28 patients on the study with adequate follow-up at the time of analysis. The phase II doses were ofatumumab 1000 mg weekly × 8 along with lenalidomide 10 mg on 21/28 days. The lenalidomide was dose adjusted according to standard dose reduction criteria. All patients were on either a daily aspirin or other anticoagulation for thrombosis (DVT) prophylaxis. Results: Thirty seven evaluable patients had adequate follow-up at the time of the analysis. The patients had a median age of 65 years (range 36–81), 76% were male, and 89% have an ECOG performance status of 0–1. The majority of patients had a relapsed indolent lymphoma with 12/37 (32%) follicular lymphoma (FL), 6/37 (16%) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 7/37 (19%) mantle cell lymphoma (MCL), one unclassifiable indolent lymphoma (3%), and 11/37 (30%) diffuse large B-cell lymphoma (DLBLC). The median duration of follow-up of surviving patients was 13 months (range 4–24). The complete response (CR) rate was 2/37 (5%) (one each FL and DLBCL) and the partial response (PR) rate was 13/37 (35%) for an overall response rate (ORR) of 15/37 (40%). The 1 year progression-free survival (PFS) was 41% (95% CI; 23–58) and the 1-year overall survival (OS) was 68% (95% CI; 49–82). In an analysis of response by patient variables, those significant included the patients with an FL histology (ORR 83%) vs. DLBCL (ORR 18%) or other(SLL, MCL, unclassifiable) (ORR 21%) (p= 0.001) and lactic dehydrogenase (LDH) normal (ORR 56%) vs. elevated (ORR 14%) (p= 0.01). In an analysis of variables for PFS, the variables with significance include diagnosis of FL (1-year PFS 67%) vs. DLBCL (9%) and SLL, MCL, unclassifiable (45%) (p=0.002), LDH normal (1-year PFS 55%) vs. elevated LDH (1-year PFS 19%), and number of prior chemotherapies 1–2 (1-year PFS 58%) vs. > 3 (1-year PFS 19%). Higher grade toxicities included grade 4 neutropenia in 9/37 (24%), one each of grade 4 bacteremia, one grade 4 DVT, stroke, and acute renal failure. Conclusions: The combination of lenalidomide and ofatumumab was well tolerated by most patients. The patients with indolent NHL had a high response rate of 83% and a 1-year PFS of 67%. Disclosures: Vose: Glaxo Smith Kline: Research Funding; Celgene: Research Funding. Off Label Use: Lenalidamide and Ofatumumab will be discussed for use in indolent and aggressive non-Hodgkin lymphoma.

scholarly journals Extended Use of Rituximab in Older Adults with Non-Hodgkin Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1279-1279
Author(s):  
Matthew J. Matasar ◽  
Coral L. Atoria ◽  
Elena B. Elkin ◽  
Chadi Nabhan
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Rural Areas ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
The United States ◽  
Non Hodgkin Lymphoma ◽  
To Receive

Abstract Background: The introduction of rituximab has improved outcomes in B-cell non-Hodgkin lymphoma (BCL) across all histologies. Extended use of rituximab, or maintenance rituximab, improves progression-free survival in follicular lymphoma (FL) patients who achieve a response to induction rituximab with or without chemotherapy, but there is no evidence of an overall survival benefit. There is currently little evidence to support extended use of rituximab in other histologic subgroups, and older patients in particular may be at risk of adverse events. Our objective was to characterize patterns and predictors of extended rituximab therapy in a population-based cohort of older BCL patients in the United States. Methods: In the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset,we identified patients 66 years and older diagnosed with BCL in 2000-2010. Histology was classified as diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), FL, mantle cell lymphoma (MCL), other indolent BCL, and BCL not otherwise specified (NOS). We identified Medicare claims for rituximab starting at any point following diagnosis. Extended rituximab therapy was defined as a duration of greater than 7 months with no gap in rituximab claims greater than 6 months. Demographic and clinical characteristics associated with extended rituximab were evaluated in multivariable logistic regression. Results: There were 24,232 BCL patients who received rituximab during the study period. The cohort was predominantly white (91%), half were men, 15% had a Charlson comorbidity score ≥2, and 12% were 85 years or older. DLBCL was the most common histology (44%), followed by FL (21%), other indolent BCL (17%), BCL-NOS (13%), MCL (6%), and BL (1%). Overall, most patients (85%) received rituximab for ≤7 months, but duration varied by histology (Table 1). More than a quarter of FL patients had extended therapy, including 7% who had rituximab for more than 24 months. Among patients with other histologies, receipt of extended therapy varied from 20% (other indolent BCL) to 8% (BL). Compared with FL patients and controlling for demographic and disease characteristics, patients with other histologies were less likely to receive extended rituximab therapy (p<0.0001). Adjusted odds ratios were 0.91 (95% CI 0.78-1.05) for MCL, 0.83 (0.75-0.91) for other indolent BCL, 0.67 (0.60-0.75) for BCL-NOS, 0.32 (0.29-0.36) for DLBCL, and 0.28 (0.15-0.53) for BL. However, 75% of patients who had extended rituximab, and 63% of those who had rituximab >24 months, were of non-FL histology. Controlling for histology and other characteristics, extended rituximab therapy was more likely among women (adjusted OR 1.09, 95% CI 1.01-1.18), and less likely among unmarried patients (0.92, 0.85-0.99) and those in rural areas (0.84, 0.75-0.94). There was significant regional variation (p<0.0001), with patients in the West (adjusted OR 0.86, 95% CI 0.79-0.95), and Midwest (0.75, 0.66-0.86) less likely to receive extended rituximab than those in the Northeast. There was no significant relationship between extended therapy and age, race, or comorbidity. Conclusions: While FL patients were more likely than others to receive extended rituximab, the majority of patients receiving extended rituximab had other diagnoses across the entire spectrum of B-cell lymphoma, for which extended rituximab is neither indicated nor supported by guidelines or prospective data. After controlling for histology, several demographic characteristics significantly influenced the duration of therapy. Extended use of rituximab – particularly in patients for whom it is not clearly indicated – may have important implications for clinical outcomes, toxicity, and costs. Table 1 Duration of rituximab use across B-cell lymphoma histologic subgroups Histology Duration of Rituximab N ≤7 mos >7-24 mos >24 mos DLBCL 10,567 91% 7% 2% FL 5,001 76% 17% 7% BL 127 92% 6% 2% MCL 1,339 79% 16% 5% Other indolent 4,095 80% 15% 5% BCL NOS 3,103 83% 13% 4% Total 24,232 80% 15% 5% Disclosures Matasar: Merck: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Honoraria; Spectrum: Honoraria. Nabhan:Celgene: Honoraria, Research Funding.

scholarly journals Real World Evidence of CAR T-Cell Therapies for the Treatment of Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma: A Monocentric Experience

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4789
Author(s):  
Beatrice Casadei ◽  
Lisa Argnani ◽  
Serafina Guadagnuolo ◽  
Cinzia Pellegrini ◽  
Vittorio Stefoni ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Objective Response ◽  
Standard Of Care ◽  
Complete Response ◽  
Cell Therapies ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T

Large B-cell lymphomas (LBCL) are the most common types of non-Hodgkin lymphoma. Although outcomes have improved thanks to the introduction of rituximab-based chemoimmunotherapy, certain LBCL still represents a challenge because of initial resistance to therapy or recurrent relapses. Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are second-generation autologous CD19-targeted chimeric antigen receptor (CAR) T-cell therapies approved for patients with relapsed/refractory (R/R) LBCL, based on the results of phase II pivotal single-arm trials ZUMA-1 (for axi-cel) and JULIET (for tisa-cel). Here, we report patients outcomes with axi-cel and tisa-cel in the standard of care (SoC) setting for R/R LBCL, treated at our Institution. Data were collected from patients who underwent leukapheresis between August 2019 and February 2021. Toxicities were graded and managed according to the institution’s guidelines. Responses were assessed as per Lugano 2014 classification. Of the 30 patients who underwent leukapheresis, 18 (60%) received axi-cel, while 12 (40%) tisa-cel. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 10% and 16% patients, respectively. Best objective and complete response rates were 73.3% and 40%, respectively. Treatment in SoC setting with CD19 CAR T-cell therapies for R/R LBCL showed a manageable safety profile and high objective response rate.

scholarly journals Antigen Glycosylation Is a Central Regulator of CAR T Cell Efficacy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1721-1721
Author(s):  
Amanda Heard ◽  
Mehmet Emrah Selli ◽  
John Lattin ◽  
Jack Landmann ◽  
Jufang Chang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Stock Options ◽  
Research Funding ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T ◽  
Complex Glycans

Abstract Chimeric antigen receptor-engineered T cells targeting CD19 (CART19) have revolutionized the management of relapsed and refractory B cell malignancies. Despite high initial response rates, many patients with acute lymphoblastic leukemia (ALL) ultimately relapse after CART19. In contrast, most patients with non-Hodgkin lymphoma experience only partial or no responses. Collectively, &lt;50% of patients treated with CART19 achieve durable disease remission. Identification of the biology responsible for these failures is central to improving CAR T cell efficacy. Several clinical reports have demonstrated that a common cause of resistance to CART19 is antigen escape, in which ALL clones emerge that have lost surface expression of CD19. The mechanisms of antigen escape that have been recognized to date all rely on disruption of CD19 genomic loci or transcribed CD19 mRNA; alterations of fully-translated CD19 protein that lead to CART19 failure have not been described. To identify pathways responsible for enabling tumor-intrinsic resistance to CART19 we performed a genome-wide loss-of-function screen in the Nalm6 ALL cell line. The second-most enriched gene in this screen was SPPL3 (Figure 1a), encoding a Golgi-resident aspartyl protease. Previous studies have determined that SPPL3 functions to broadly limit protein glycosylation by cleaving glycosyltransferases from the Golgi membrane, impairing their ability to add complex glycans to proteins as they pass through the Golgi (Voss M. et al. EMBO, 2014). Using targeted genomic disruption, we confirmed that loss of SPPL3 results in resistance to CART19 in human ALL and non-Hodgkin lymphoma models (Figures 1b-c). CART19 cells exposed to SPPL3KO ALL demonstrated significantly lower expression of CD69, PD1, Tim3 and CD107a, as well as less activation of the central T cell transcription factors NFAT and NFκB, indicating a global suppression of T cell stimulation. Consistent with its known function, loss of SPPL3 resulted in increased addition of complex glycans to CD19. Surface staining of SPPL3KO cells revealed that CD19 antibodies were less capable of binding this hyperglycosylated CD19. This included decreased binding of the antibody used to construct the anti-CD19 CAR (clone FMC63). Protein modeling revealed that an asparagine residue known to be normally glycosylated on CD19 (N125) is in close physical proximity to the FMC63 binding site (Figure 1d), suggesting that the addition of complex glycans at this site may be responsible for disruption of CAR binding that led to impaired T cell activation. We next turned our attention to CD22, another B cell antigen that is normally glycosylated and the target of CAR therapy. In contrast to CD19, loss of SPPL3 had no impact on CD22 glycosylation or antibody binding. Similarly, loss of SPPL3 did not enable resistance to CD22-targeted CAR T cells. These findings substantiated our hypothesis loss of SPPL3 lead to CART19 failure directly via modifying CD19 glycosylation, and not through another CD19-independent mechanism. To further validate the impact of CD19 glycosylation in regulating CART19 efficacy, we over-expressed SPPL3 in ALL cells, previously shown to promote global hypoglycosylation. We confirmed decreased glycosylation of CD19 (Figure 1e), and found that this resulted in loss of FMC63 binding to CD19 and complete resistance to CART19 activity (Figure 1f). In summary, our findings identify that changes to CD19 glycosylation, either enhanced or decreased, impair the ability of CARs to bind and initiate T cell effector function against malignant B cells. Further, these data identify post-translational protein modification as a novel mechanism of antigen escape from CAR-based T cell immunotherapy. Figure 1 Figure 1. Disclosures Ruella: AbClon: Consultancy, Research Funding; viTToria biotherapeutics: Research Funding; BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties; Tmunity: Patents & Royalties. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding.

scholarly journals Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma

2020 ◽  
Vol 4 (17) ◽  
pp. 4091-4101
Author(s):  
Arne Kolstad ◽  
Tim Illidge ◽  
Nils Bolstad ◽  
Signe Spetalen ◽  
Ulf Madsbu ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Hematologic Toxicity ◽  
Overall Response ◽  
Non Hodgkin Lymphoma ◽  
Anti Cd20

Abstract For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20–based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the “cold” anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.

scholarly journals Efficacy and Safety of JWCAR029 in Adult Patients with Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4187-4187 ◽  
Author(s):  
Zixun Yan ◽  
Wen Wang ◽  
Zhong Zheng ◽  
Ming Hao ◽  
Su Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Level ◽  
Car T Cells ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T

Abstract Introduction JWCAR029 is a novel CD19-directed 4-1BB stimulated chimeric antigen receptor T (CAR-T) cell type, which is different from JWCAR017 with independent production of CD4 and CD8 T cells and transfusion in non-fixed ratio. We conducted a single arm, open-label, dose escalation Phase I trial of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma (NCT03355859). Methods From January to July 2018, 10 patients have been enrolled in this trial, including eight diffused large B cell lymphoma (DLBCL) and two MALT lymphoma, with median age of 47 years (range 32 to 59 years). All the patients received immunochemotherapy as induction and more than two lines of salvage treatment. Two patients received bridging chemotherapy after T-cell collection due to rapid tumor progression, followed by re-evaluation before CAR-T cell infusion. Lymphodepletion preconditioning was accomplished by fludarabine 25mg/m2/d and cyclophosphamide 250mg/m2/d on Day-4 to D-2, followed by CAR-T cell infusion on Day0. JWCAR029 was administrated as a single infusion in escalation dose levels, from 2.5×107 CAR-T cells (dose level 1, DL1) to 5.0×107 CAR-T cells (dose level 2, DL2) and to 1.0×108 CAR-T cells (dose level 3, DL3) according to mTPI-2 algorithm. Circulating blood count, serum biochemistry, and coagulation status were follow-up after infusion. Cytokines were assessed on a Luminex platform. Tumor evaluation was performed on Day 29 by PET-CT. PK data were detected by flow cytometry and real-time quantitative polymerase chain reaction system. All the adverse events were recorded. The study was approved by the Shanghai Rui Jin Hospital Review Board with informed consent obtained in accordance with the Declaration of Helsinki. Results The demographic characteristics of the patients were demonstrated in Table 1. Among six evaluable patients (3 of DL1 and 3 of DL2), the ORR was 100% on Day 29, including four complete remission and 2 partial remission. Cytokine release syndrome (CRS) was 100% in Gr 1, with main symptoms as fever (<39.0 degrees), fatigue, and muscle soreness. No neurotoxicity was observed. Four of the six patients with fever >38.0 degrees used prophylactic IL-6 Inhibitor (8mg/kg, ACTEMRA, two patients administered twice). No patients received steroids. The CRS showed no difference between dose level groups (p>0.99). Adverse effects included leukopenia (Gr 3-4: 83.3%, Gr 1-2: 16.7%), hypofibrinogenemia (Gr 1: 16.7%, Gr 2-4: 0%), liver dysfunction (Gr 1: 33.3%, Gr 2-4: 0%), elevated CRP (Gr 1: 83.3%, Gr 2-4: 0%), ferritin (Gr 1-2: 83.3%, Gr 2-4: 0%), or IL-6 (Gr 1-2:100%, Gr 3-4: 0%, Table 2). Conclusion Although long-term follow-up was needed, the preliminary data of six patients in this trial have demonstrated high response rates and safety of JWCAR029 in treating relapsed and refractory B-cell non-Hodgkin lymphoma. Disclosures Hao: JW Therapeutics: Employment, Equity Ownership.

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